6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one, composition and use

ABSTRACT

This invention relates to 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-ones and -ols of the formula ##STR1## wherein X is ##STR2## or loweralkyl; Y is hydrogen, halogen, loweralkyl, loweralkoxy, trifluoromethyl, nitro or amino; R is H when the bond between the oxygen atom and the carbon atom in question is a single bond; otherwise the dotted line signifies part of a double bond to the oxygen atom; R 1  is hydrogen, loweralkyl or arylloweralkyl; R 2  and R 3  are independently hydrogen, loweralkyl or arylloweralkyl, or R 2  and R 3  taken together with the nitrogen atom form an optionally substituted heterocycle selected from the group consisting of piperidinyl, pyrtolidinyl, morpholinyl, imidazol-1-yl, 1-piperazinyl, said substituents being hydrogen or loweralkyl; 4-substituted-1-piperazinyl of the formula where R 6  is loweralkyl, aryl, arylloweralkyl, ##STR3## 2-pyrimidyl, ##STR4## 2-pyridinyl of the formula ##STR5## or 4-pyridinyl of the formula ##STR6## 4-substituted-1-piperidinyl of the formula ##STR7## wherein R 7  is hydrogen, loweralkyl, aryl, arylloweralkyl, 2-pyridinyl of the formula ##STR8## 4-pyridinyl of the formula ##STR9## 2-pyrimidinyl of the formula    arylcarbonyl, ##STR10## R 8  is hydrogen or --OH; R 4  is hydrogen, loweralkoxycarbonyl or aryloxycarbonyl; Z is chlorine, bromine or fluorine; m is an integer of 1 to 4; n is an integer of 1 to 4 or a pharmaceutically acceptable acid addition salt thereof and where applicable the geometric and optical isomers and racemic mixtures thereof. The compounds of this invention display utility as antipsychotic agents and analgesic agents.

This is a division of application Ser. No. 843,330 filed Feb. 28, 1991,now U.S. Pat. No. 5,180,834 which is a division of U.S. Ser. No. 692,341filed Apr. 26, 1991, now U.S. Pat. No. 5,114,936, which is acontinuation-in-part of U.S. Ser. No. 571,482 filed Aug. 23, 1990, nowabandoned.

This invention relates to 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-ones and -ols of the formula ##STR11## wherein Xis ##STR12## or loweralkyl; Y is hydrogen, halogen, loweralkyl,loweralkoxy, trifluoromethyl, nitro or amino; R is H when the bondbetween the oxygen atom and the carbon atom in question is a singlebond; otherwise the dotted line signifies part of a double bond to theoxygen atom; R₁ is hydrogen, loweralkyl or arylloweralkyl; R₂ and R₃ areindependently hydrogen, loweralkyl or arylloweralkyl, or R₂ and R₃ takentogether with the nitrogen atom form an optionally substitutedheterocycle selected from the group consisting of piperidinyl,pyrrolidinyl, morpholinyl, imidazol-1-yl, 1-piperazinyl, saidsubstituents being hydrogen or loweralkyl; 4-substituted-1-piperazinylof the formula ##STR13## R₈ is hydrogen or --OH; R₄ is hydrogen,loweralkoxycarbonyl or aryloxycarbonyl; Z is chlorine, bromine orfluorine; m is an integer of 1 to 4; n is an integer of 1 to 4 or apharmaceutically acceptable acid addition salt thereof and whereapplicable the geometric and optical isomers and racemic mixturesthereof. The compounds of this invention display utility asantipsychotic agents and analgesic agents.

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric and stereoisomers andracemic mixtures where such isomers and mixtures exist.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1to 6 carbon atoms. Examples include methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl and straight and branched chain pentyl andhexyl.

The term aryl shall mean a phenyl group optionally substituted with oneor more halogen, loweralkyl, loweralkoxy or trifluoromethyl groups,including m-methoxyphenyl.

The term halogen shall mean fluorine, chlorine, bromine or iodine.

The compounds of the present invention, wherein X is phenyl, areprepared in the following manner. The substituents R, R₁, R₂, R₃, R₄, X,Y and Z and the integers m and n are as defined above unless indicatedotherwise.

A substituted benzaldehyde is selected having the formula ##STR14## Suchbenzaldehydes are well known or can be synthesized by conventionaltechniques well known by one of ordinary skill in the art. Compound IIis reacted with hydroxylaniine hydrochloride, under conventional oximeformation conditions, to form the oxime, Compound III, having theformula ##STR15## Typically, this reaction is conducted in a basicaromatic solvent, such as pyridine, picoline or collidine, at about roomtemperature to 100° C. for 0.5 to 2 hours.

Oxime III is reacted with a halogen such as Cl₂ or Br₂ to form ahalo-oxime of the formula ##STR16## where Hal is a halogen selected fromCl and Br. Typically, this reaction is conducted in an inert solventsuch as dichloromethane, chloroform or 8N HCI at a temperature of from0° to 15° C. Gaseous halogen, e.g. Cl₂, is bubbled into the reaction atsuch a rate as to maintain the reaction temperature below 15° C. Thehalogen is bubbled in for a time period of from about 2 to 10 minuteswhereafter; when the solvent is not 8N HCl, a triethylamine/solventsolution is added dropwise during further bubbling of the gaseoushalogen until no further color changes are observed.

Compound IV is reacted with Compound V of the formula ##STR17## to formCompound (VI) of the formula ##STR18##

Compound V is well known or can be synthesized by conventionaltechniques well known by one of ordinary skill in the art. For example,Compound V can be prepared following the techniques of Edward J. Cone etal., J. Organic Chemistry 37, No. 26, 4436 (1972). Typically, a1,3-cyclohexanedione of the formula ##STR19## in an inert solvent, sucha benzene or toluene, under a nitrogen atmosphere at reflux for 1 to 2hours to obtain Compound V.

Compound IV is combined with Compound V, contained in an inert solventsuch as dichloromethane or chloroform in the presence of triethylamine,present in an amount of 2 to 3 equivalents, at ambient temperature for18 to 24 hours to obtain Compound VI.

Compound VI is reacted with an amine of the formula ##STR20## in thepresence of paraformaldehyde to form Compound VIII of the inventionhaving the formula ##STR21## Typically, this reaction is conducted in analkanolic solvent such as methanol, ethanol or isobutanol at atemperature of 25° to 100° C. for 1 to 24 hours. Alternatively CompoundVIII is formed by reacting Compound VI with an amine IX of the formula##STR22## in the presence of a strong organic acid such astrifluoroacetic or methanesulfonic acid. Typically, the reaction isconducted with the organic acid as solvent, at a temperature of 0° to100° C. for 1 to 12 hours.

Compound VIII, where R₂ and R₃ are alkyl, may undergo a displacementreaction with a higher boiling amine, such as a base containing aheterocyclic group, e.g. a pipendinyl, pyrrolidinyl, morpholinyl,1H-imidazol-1-yl, 1 -piperazinyl, 4-substituted-1-piperazinyl or4-substituted-1-piperidinyl group to form Compound X of the invention ofthe formula ##STR23## where R₅ is the heterocyclic group.

An intermediate in this reaction is the 5-methylene derivative (Xa) ofthe formula ##STR24## Compound Xa can be prepared independently bytreating Compound VIII first with excess methyl iodide and then with abase such as aqueous sodium bicarbonate. In an alternative preparationof Compound X, Compound Xa is subjected to an addition reaction with thehigher boiling amine, such as the base containing a heterocycle, asdescribed above.

An alternative preparation is as follows.

Compound VI is lithiated, under conventional lithiation techniques andconditions, i.e., by reaction with an organic lithiation agent, such aslithium diisopropylamide, lithium bis(trimethylsilyl)amide or lithiumdicyclohexylaniide in an ethereal solvent, such as diethyl ether,tetrahydrofuran or dimethoxyethane, at a temperature of -78° to 250° C.for 0.15 to 3 hours, in an inert atmosphere, e.g. nitrogen atmosphere,to form Compound XI of the formula ##STR25## Compound XI in turn isreacted with a dihaloalkane of the formula Hal--(CH₂)_(m) --Hal (XII),where each Hal is independently Cl, F, Br or I, e.g.,1-chloro-3-iodopropane, to form compound XIII of the formula ##STR26##

Alternatively, compound XI may be reacted with a halo alkyl or halo arylformate of the formula Hal--COO--R₁₀, where Hal is Cl or Br and R₁₀ isloweralkyl or aryl, to form compound XIIIa of the formula ##STR27##Typically, these reactions are carried out in an ethereal solvent suchas diethylether, tetrahydrofuran or dimethoxyethane at a temperature of-78° to 25° C. for 0.5 to 24 hours.

Compound XIIIa may be further reacted with a dihaloalkane of the formulaXII described above to form compound XIIIb having the formula ##STR28##

Typically, this reaction is carried out in a polar solvent such asacetone, methanol or acetonitrile in the presence of a base such aspotassium carbonate, sodium carbonate, or sodium methoxide at atemperature of 0° to 100° C. for 1 to 24 hours.

The resultant Compounds XIII are then reacted with an amine of theformula ##STR29## to form a compound of the invention XIV having theformula ##STR30##

Compounds VIII, X and XIV (where R₄ =H) may be reduced in a conventionalmanner, such as with a metal hydride, e.g. NaBH₄ or LiBH₄ underconventional reducing conditions to form Compounds VIII(a), X(a) andXIV(a), respectively, having the formula, ##STR31## Compound XIII can belithiated, in the manner described above, whereafter a haloalkane of theformula R₉ Hal where R₉ is loweralkyl and Hal is a halogen selected fromCl, Br and I, is reacted with the lithiated compound, in a conventionalmanner, to obtain Compound XV where R₁ is lower alkyl. Typically, thereaction is carried out in an ethereal solvent such as diethyl ether,tetrahydrofuran or 1,2-dimethoxyethane at a temperature of -78° to 250°C. for 0.5 to 24 hours. ##STR32##

Compounds where X is loweralkyl may be prepared in like manner as thecompounds where X is ##STR33## as illustrated on pages 4-10.

The compounds of the present invention are useful for treating psychosesby virtue of their ability to elicit an antipsychotic response inmammals.

Antipsychotic activity is determined in the Climbing Mice Assay by amethod similar to that described by P. Protais, et al.,Psychophannacol., 5.0 1 (1976) and B. Costall, Eur. J. Pharmacol., 50,39 (1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4"×10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes.

Compounds to be tested for antipsychotic activity are injectedintraperitoneally or given orally at various time intervals, e.g. 30minutes, 60 minutes, etc. prior to the apomorphine challenge at ascreening dose of 10-60 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________    Climbing Behavior    Mice With             Score    ______________________________________    4 paws on bottom (no climbing)                          0    2 paws on the wall (rearing)                          1    4 paws on the wall (full climb)                          2    ______________________________________

Mice consistently climbing before the injection of apomorphine will bediscarded.

With full-developed apomorphine climbing, the animals are hanging on tothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a linear regressionanalysis, of some of the compounds of the instant invention as well as astandard antipsychotic agent are presented in Table I.

                  TABLE I    ______________________________________    CLIMBING MOUSE ASSAY    COMPOUND               (ED.sub.50 mg/kg, ip)    ______________________________________    6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-                           15.0    1-piperazinyl)-propyl]-3-phenyl-1,2-    benzisoxazol-4(5H)-one dihydrochloride    6,7-dihydro-5-[3-(4-(4-fluorophenyl)-1-                           6.36    piperidinyl)-propyl]-3-phenyl-1,2-    benzisoxazol-4(5H)-one hydrochloride    6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-                           2.9    piperidinyl)-propyl]-3-(2-fluorophenyl)-    1,2-benzisoxazol-4(5H)-one hydrochloride    6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-                           6.2    piperidinyl)-propyl]-3-(4-fluorophenyl)-    1,2-benzisoxazol-4(5H)-one hydrochloride    6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-                           5.7    piperidinyl)-propyl]-3-(3-fluorophenyl)-    1,2-benzisoxazol-4(5H)-one hydrochloride    clozapine (standard)   9.0    ______________________________________

Antipsychotic response is achieved when the compounds of the presentinvention are administered to a subject requiring such treatment of aneffective oral, parenteral or intravenous dose of from 0. 10 to 50 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosage range set forthherein is exemplary only and does not, to any extent, limit the scope orpractice of the invention.

Compounds of the present invention are also useful as analgesics due totheir ability to alleviate pain in mammals as demonstrated in thephenyl-p-quinone writhing assay in mice, a standard assay for analgesia[Proc. Soc. Exptl. Biol, Med. 95, 729 (1957)]

The analgesic activity of some of the compounds of the present inventionexpressed in terms of an ED₅₀ inhibition of wrathing are given below inTable II.

                  TABLE II    ______________________________________                         ED.sub.50                         Inhibition of Writhing    Compound             mg/kg, s.c    ______________________________________    6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-                         5.18    1-piperazinyl)-propyl]-3-phenyl-1,2-    benzisoxazol-4(5H)-one dihydrochloride    6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-                         3.99    1-piperidinyl)-propyl]-3-phenyl-1,2-    benzisoxazol-4(5H)-one hydrochloride    propoxyphene (standard)                         3.90    ______________________________________

The analgesic relief is achieved when the compounds of the invention areadministered to a subject requiring such treatment at an effective oral,parenteral or intravenous dose of from 0.1 to 25 mg/kg of body weightper day. A preferred effective dose within this range is from about 1 to10 mg/kg of body weight per day. It is to be understood, however, thatfor any particular subject, specific dosage regimens should be adjustedaccording to the individual need. It is further to be understood thatthe dosages set forth herein are examples only and that they do not toany extent limit the scope of the practice of the invention.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one or -ol derivative of theinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in suchcompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that an oral dosage unit form contains between 5.0-300milligrams of the 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one or -olderivative of the present invention.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present compounds, suctose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of the6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one or -ol derivative of theinvention, but may be varied to be between 0.1 and about 50% of theweight thereof. The amount of the inventive compound present in suchcompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that a parenteral dosage unit contains between 5.0 to 100milligrams of the 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one or -olderivative of the invention.

The solutions or suspensions may also include the following adjuvants: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

Examples of some of the compounds of the invention include:

6,7-Dihydro-3-phenyl-5-[2-(1-piperidinyl)-ethyl]-1,2-benzisoxazol-4(5H)-one

6,7-Dihydro-3-(4-fluorophenyl)-5-[2-(2-methyl-1H-imidazol-1-yl)-ethyl]-1,2-benzisoxazol-4(5H)-one;

3-(3-Chlorophenyl)-6,7-dihydro-5-[2-2(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-7-methyl-1,2-benzisoxazol-4(5H)-one;

6,7-Dihydro-3-(3-fluorophenyl)-5-[(4-methyl-1-piperazinyl)-methyl]-1,2-benzisoxazol-4(5H)-one;

3-(2-Chlorophenyl)-6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyll-1,2-benzisoxazol-4(5H)-one;

3-(3-Chlorophenyl)-6,7-dihydro-5-[2-(1-pyffolidinyl)-ethyl]1,2-benzisoxazol-4(5H)-one;

6,7-Dihydro-5-(4-dimethylaminobutyl)-3-phenyl-1,2-benzisoxazol-4(5H)-one;

6,7-Dihydro-5-(3-dimethylaminopropyl)-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one;

3-(3-Chlorophenyl)-6,7-dihydro-5-[4-(1-piperidinyl)-butyl]-1,2-benzisoxazol-4(5H)-one;

6,7-Dihydro-3-(3-fluorophenyl)-7-methyl-5-[4-(1-pyrrolidinyl)-butyl]-1,2-benzisoxazol-4(5H)-one;

6,7-Dihydro-3-(3-fluorophenyl)-5-[2-(4-(2-methoxyphenyl)-1-piperazinyl)-ethyl]-1,2-benzisoxazol-4(5H)-one;

3-(3-Fluorophenyl)-4-hydroxy-5-[4-methyl-1-piperazinyl)-butyll-4,5,6,7-tetrahydro-1,2-benzisoxazole.

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein. All temperaturesare given in degrees centigrade unless indicated otherwise.

EXAMPLE 16,7-Dihydro-5-(4-morpholinvlmethyl)-3.1)henyl-192-benzisoxazol-4(5H)-one

6,7-Dihydro-3-phenyl- 1,2-benzisoxazol-4(5H)-one, (2.0 g) was refluxedin 50 ml isobutanol containing 2.0 g morpholine·HCl, 1.0 gparaformaldehyde and 1 ml concentrated hydrochloric acid. After 7 hoursat reflux, an additional 0.5 g paraformaldehyde was added and thereaction was allowed to reflux an additional 21 hours. The solvent wasremoved under reduced pressure and the residue distributed between etherand 5% HCl. The aqueous phase was separated, washed with additionalether and then made basic with solid NaHCO₃. The product was extractedinto 1:1 ether/ethyl acetate and isolated by evaporation of the solventunder reduced pressure to give 1.82 g of6,7-dihydro-5-(4-morpholinylmethyl)-3-phenyl-1,2-benzisoxazol-4(5H)-one,m.p. 140°-141° C.

Analysis: Calculated for C₁₈ H₂₀ N₂ O₃ : 69.21%C, 6.45%H, 8.97%N. Found:69.18%C, 6.48%H, 8.90%N.

EXAMPLE 26,7-Dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-onehydrochloride

Bis-dimethylaminomethane (0.51 g) was added to 2.5 ml of trifluoroaceticacid which had been previously chilled to -10° C.6,7-Dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (1.0 g) was then addedand the reaction was warmed for 1 hour at 100° C. and then allowed tostand an additional 2 days at room temperature. The reaction mixture waspoured into 5% HCl and washed with ether, after which the aqueous phasewas treated with solid sodium bicarbonate until basic. Extraction withether followed by drying and concentration gave an oil. Thehydrochloride was formed in etheiral HCl and was recrystallized fromdichloromethane/ether to give 0.95 g of6,7-dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-onehydrochloride, m.p. 1 178°-180° C.

Analysis: Calculated for C₁₆ H₁₈ N₂ O₂ ·HCl: 62.64%C, 6.24%H, 9.31%N.Found: 62.40%C, 6.22%H, 9.03%N.

EXAMPLE 3 6,7-Dihydro-5-(1-piperidinylmethyl)-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride hemihydrate

6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazol-4(5H)-onehydrochloride (0.80 g) was warmed with 5 ml of piperidine (4.31 g) at90° C. for 20 minutes. The excess piperidine was removed in vacuo andthe hydrochloride was formed in ethereal HCl to give 0.95 g of6,7-dihydro-5-(1-piperidinylmethyl)-3-phenyl-1,2-benzisoxazol-4(5H)-onehydrochloride hemihydrate, m.p. 182°-1830° C.

Analysis: Calculated for C₁₉ H₂₂ N₂ O₂ ·HCl·0.5 H₂ O: 64.12%C, 6.80%H,7.87%N. Found: 63.81%C, 6.52%H, 7.71%N.

EXAMPLE 4cis-5-(Dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazolehydrochloride

6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazol-4(5H)-onehydrochloride (7.5 g) was dissolved in 100 ml ethanol and treated with5.0 g sodium borohydride. After stirring for 1 hour the reaction mixturewas distributed between 5% HCl and ether. The aqueous phase was thenmade basic with solid sodium bicarbonate and extracted with ether.Concentration under reduced pressure gave the product as a mixture oftrans and cis isomers which was chromatographed by preparative highpressure liquid chromatography (HPLC) (ethyl acetate/CH₃CN/diethylamine; 90:10:1) to give 2.20 g of the pure cis isomer. Thehydrochloride was formed in HCl/ether and then recrystallized frommethanol/ether to give 1.81 g ofcis-5-(dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazolehydrochloride, m.p. 235°-236° C.

Analysis: Calculated for C₁₆ H₂₀ N₂ O₂ ·HCl: 62.23%C, 6.86%H, 9.07%N.Found: 62.14%C, 6.89%H, 8.89%N.

EXAMPLE 5trans-5-(Dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazolehydrochloride

6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazol-4(5H)-onehydrochloride (7.5 g) was dissolved in 100 ml ethanol and treated with5.0 g sodium borohydride. After stirring for 1 hour the reaction mixturewas distributed between 5% HCl and ether. The aqueous phase was thenmade basic with solid sodium bicarbonate and extracted with ether.Concentration under reduced pressure gave the product as a mixture oftrans and cis isomers which was chromatographed by preparative HPLC(ethyl acetate/CH₃ CN/diethylamine; 90:10:1) to give 3.31 g of the puretrans isomer. The hydrochloride was formed in HCl/ether and thenrecrystallized from methanol/ether to give 2.90 g oftrans-5-(dimethylaminomethyl)-4-hydroxy-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, m.p. 231°-232° C.

Analysis: Calculated for C₁₆ H₂₀ N₂ O₂ ·HCl: 62.23%C, 6.86%H, 9.07%N.Found: 61.72%C, 6.71%H, 9.00%N.

EXAMPLE 6 a. 6,7-Dihydro-5-methylene-3-phenyl-1,2-benzisoxazol-4(5H)-one

6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazole- 4(5H)-onefree base (3.0 g) was dissolved in 3 ml of methanol and added in oneportion to 5 ml (excess) of methyl iodide. As the quaternary iodidebegan to separate, additional methanol was added to facilitate stirring.After stirring overnight the reaction mixture was poured into 5% sodiumbicarbonate solution and extracted with ether. The organic phase waswashed with 5% HCl and then dried, evaporated, and recrystallized fromhexane to give 2.05 g of6,7-dihydro-5-methylene-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p.97°-990° C.

Analysis: Calculated for C₁₄ H₁₁ NO₂ : 74.65%C, 4.92%H, 6.22%N. Found:74.96%C, 5.10%H, 6.21%N.

b.6,7-Dihydro-5-[(4-methyl-1-piperazinyl)-methyll-3-phenyl-1,2-benzisoxazol-4(5H)-onedihydrochloride

In 5 ml (excess) N-methylpiperazine was added 2.65 g of6,7-dihydro-5-methylene-3-phenyl-1,2-benzisoxazol-4(5H)-one. The mixturewas heated with steam to dissolve the solid completely, then the excessN-methylpiperazine was vacuum distilled off. The residue was dissolvedin ether, then dried over MgSO₄ and filtered. The dihydrochloride saltwas precipitated from solution by adding excess ethereal HCl. Theprecipitate was filtered and recrystallized from 7:1 isopropanol/waterto yield 3.59 g of6,7-dihydro-5-[(4-methyl-1-piperazinyl)-methyl]-3-phenyl-1,2-benzisoxazol-4(5H)-onedihydrochloride, m.p. 225° C. (dec).

Analysis: Calculated for C₁₉ H₂₃ N₃ O₂ ·2HCl: 57.29%C, 6.33%H, 10.55%N.Found: 57.37%C, 6.35%H, 10.48%N.

EXAMPLE 7 a. 3-Morpholino-2-cyclohexen-1-one

In 700 ml benzene was dissolved 40.0 g 1,3-cyclohexanedione and 62 mlmorpholine. The resulting solution was heated at reflux under nitrogenatmosphere for 1.5 hours. The water present in the reaction mixture wascollected using a Dean-Stark trap. Upon cooling to room temperature, thereaction mixture was filtered through alumina and the filtrateconcentrated in vacuo. Trituration of the resulting oil with ethersolidified 62.4 g of 3-morpholino-2-cyclohexen-1-one crystals.

b. 2-Fluorobenzaldehyde oxime

In 200 ml pyridine was dissolved 50.0 g 2-fluorobenzaldehyde and 42.0 ghydroxylamine hydrochloride at room temperature with stirring. Theresulting solution was heated on a steam bath for two hours. Uponcooling to room temperature, the reaction mixture was poured into 5% HCland ether. The layers were separated and the organic phase was washedfour times with 5% HCl followed by a final wash with brine. The organiclayer was dried (Na₂ SO₄) filtered and concentrated in vacuo to give55.0 g of an oil which solidified on standing to yield2-fluorobenzaldehyde oxime.

c. 2-Fluoro-N-hydroxybenzenecarboximidoyl chloride

In 1 liter dichloromethane was dissolved 55.0 g 2-fluorobenzaldehydeoxime at room temperature with stirring. The resulting solution wascooled to -10° C. and Cl₂ was bubbled in at such a rate to maintain thetemperature below 15° C. After a dark blue color was generated (2-3minutes) a solution of triethylamine (50 ml) in dichloromethane (100 ml)was added dropwise concurrently with Cl₂ addition. When the reactionmixture had maintained a yellow color, additions of the triethylaminesolution and Cl₂ were discontinued. Concentration of the reactionmixture left an oil which was dissolved in ether and washed four timeswith 3N HCl followed by a final wash with brine. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo to give 60.0 g of2-fluoro-N-hydroxybenzenecarboximidoyl chloride as an oil whichsolidified on standing.

d. 6,7-Dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

In 450 ml dichloromethane were combined 62.6 g3-morpholino-2-cyclohexen-1-one and 96 ml triethylamine at roomtemperature with stirring. The reaction mixture was kept under nitrogenatmosphere and a solution of 60.0 g 2-fluoro-N-hydroxybenzenecarboximidoyl chloride in 178 ml dichloromethane wasadded dropwise over five hours. The resulting solution was concentratedin vacuo to an oil which was dissolved in ether and washed three timeswith 3N HCl followed by a final wash with brine. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo to give an oil. Columnchromatography on silica (dichloromethane as eluant) gave 20.0 g of anoil which solidified on standing to yield6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol -4(5H)-one, m.p. 82°-83°C. after recrystallization from ether-hexane.

Analysis: Calculated for C₁₃ H₁₀ FNO₂ : 67.53%C, 4.36%H, 6.06%N. Found:67.56%C, 4.37%H, 6.01%N.

e. 6,7-Dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride

Trifluoroacetic acid (20 ml) was chilled to -10° C. (ice-methanol) andthen bisdimethylaminomethane (2.55 g) was added, followed by6,7-dihydro-3-(2-fluorophenyl) -1,2-benzisoxazol-4(5H)-one (4.60 g). Thereaction mixture was warmed at 90° C. for 6 hours and then poured into5% HCl and washed two times with ether. The aqueous phase was made basicwith solid sodium bicarbonate and then extracted with ether. Drying andevaporation gave the product as an oil. The hydrochloride was formed inethereal HCl and then recrystallized from methanol/ether to give 3.55 gof6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride, m.p. 177°-1790° C.

Analysis: Calculated for C₁₆ H₁₇ FN₂ O₂ ·HCl: 59.16%C, 5.59%H, 8.63%N.Found: 59.06%C, 5.65%H, 8.61%N.

EXAMPLE 8 6,7-Dihydro-3-(2-fluorophenyl)-5-[(2-methyl-1H-imidazol-1-yl-methyll-1,2-benzisoxazol-4(5H)-onemaleate

6,7-Dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (5.0 g) and 2-methylimidazole (2.65 g) were dissolvedin 50 ml of water and the mixture was brought to reflux. After heatingfor 16 hours the reaction mixture was distributed between CH₂ Cl₂ and 5%HCl and then the aqueous phase was washed once more with CH₂ Cl₂. Theaqueous phase was then basified with solid sodium bicarbonate andextracted with ether. The organic phase was then dried and evaporated togive the product as an oil. The maleate was formed in methanol/ether andthen recrystallized from methanol/ether to give 2.0 g of6,7-dihydro-3-(2-fluorophenyl)-5-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2-benzisoxazol-4(5H)-one maleate, m.p. 143°-145° C.

Analysis: Calculated for C₁₈ H₁₆ N₃ O₂ ·C₄ H₄ O₄ :59.86%C,4.56%H,9.52%N. Found: 59.65%C, 4.54%H, 9.43%N.

EXAMPLE 9 a.5-(3-Chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one

In 478 ml anhydrous tetrahydrofuran (THF) was dissolved 10.2 g6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogenatmosphere with stirring. The solution was cooled to -78° C. and 47.8 mllithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise.The resulting solution was stiffed for 10 minutes at -78° C. and 7.7 ml1-chloro-3-iodopropane was added. Upon warming to room temperature, thereaction mixture was poured into water and ether. The layers wereseparated and the aqueous phase was extracted twice with dichloromethaneand twice with ether. The combined organic layers were washed with brineand dried (MgSO₄). Filtration and concentration gave the crude product.Column chromatography on silica gel (10% ethyl acetate/hexane) gave 6.2g of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one.

b.6,7-Dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-onesalicylate

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.75g) and dimethylformamide (37.0 ml) was added diisopropylethyl amine(6.81 ml), pyrrolidine (2.17 ml) and sodium iodide (5.85 g) at roomtemperature with stirring. The reaction was flushed with nitrogen andwarmed at 73°-76° C. for 1.25-2 hours. Upon cooling to room temperature,dilute aqueous sodium bicarbonate and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous layerextracted twice with ethyl acetate and once with ether. The combinedorganic layers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via flash columnchromatography (silica gel, 2% triethylamine/0-1.0% methanol/ether)afforded 3. 10 g of6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyll-1,2-benzisoxazol-4(5H)-oneas an oil which solidified on standing. The salicylate was prepared with1.07 eq. salicyhc acid in ether. The resulting solid was redissolvedwith methanol. Addition of pentane led to precipitation of the targetsalt. Filtration and washing with pentane gave6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-onesalicylate, m.p. 106°-107° C.

Analysis: Calculated for C₂₇ H₃₀ N₂ O₅ : 70.11%C, 6.54%H, 6.06%N. Found:70.09%C, 6.54%H, 6.04%N.

EXAMPLE 10 6,7-Dihydro-5-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.80g) and dimethylformamide (57.0 ml) was added 2-methylimidazole (3.30 g),diisopropylethyl amine (10.5 ml) and sodium iodide (9.04 g) at roomtemperature with stirring. The reaction was flushed with nitrogen andwarmed at 76° C. for 1 hour. Upon cooling to room temperature, diluteaqueous sodium bicarbonate and ethyl acetate were added to the reactionmixture. The layers were separated and the aqueous layer extracted twicewith ethyl acetate and once with ether. The combined organic layers werewashed with brine and concentrated to give the crude product. Drying wasaccomplished by azeotroping with benzene. Purification via flash columnchromatography (silica gel, 2% triethylamine/0-20% methanol/ether)afforded 2.70 g (40%) of6,7-dihydro-5-[3-(2-methyl-1H-imidazol-1-yl)-propyll-3-phenyl-1,2-benzisoxazol-4(5H)-one. Recrystallization fromdichloromethane/ether/pentane gave the product, m.p. 97°-99° C.

Analysis: Calculated for C₂₀ H₂₁ N₃ O₂ : 71.62%C, 6.31%H, 12.53%N.Found: 71.46%C, 6.32%H, 12.42%N.

EXAMPLE 11 6,7-Dihydro-5-[3-(4-morpholinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.70g) and dimethylfortnamide (56 ml) was added diisopropylethyl amine (8.06ml), morpholine (3.44 ml) and sodium iodide (8.86 g) at room temperaturewith stirring. The reaction was flushed with nitrogen and warmed at78°-80° C. for 2.75-3 hours. Upon cooling to room temperature, water andethyl acetate were added to the reaction mixture. The layers wereseparated and the aqueous layer extracted thrice with ethyl acetate andonce with ether. The combined organic layers were washed with brine anddried (Na₂ SO₄). Filtration and concentration gave the crude product.Purification via flash column chromatography (silica gel, 2%triethylamine/0-5% methanol/ether) afforded 2.62 g of the product.

Recrystallization from ether/pentane gave6,7-dihydro-5-[3-(4-morpholinyl)propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 86°-88.5° C.

Analysis: Calculated for C₂₀ H₂₄ N₂ O₃ : 70.57%C, 7.11%H, 8.23%N. Found:70.47%C, 7.12%H, 8.14%N.

EXAMPLE 12 6,7-Dihydro-5-13-(4-methyl-1-piperazinyl) -propyll-3-phenyl-1,2-benzisoxazol-4(5H)-one dihydrochloride

To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.90 g) and dimethylformamide (67.0 ml) wasadded disopropylethyl amine (4.70 ml), 1 -methylpiperazine (2.25 ml),and sodium iodide (4.05 g), at room temperature, with stirring. Thereaction was flushed with nitrogen and warmed at 96°-98° C. for 2.5-3hours. Upon cooling to room temperature, dilute aqueous sodiumbicarbonate and ethyl acetate were added to the reaction mixture. Thelayers were separated and the aqueous layer extracted twice with ethylacetate and once with ether. The combined organic layers were washedwith brine and dried (MgSO₄). Filtration and concentration gave thecrude product. Purification via flash column chromatography (silica gel,2% triethylamine/5% methanol/ether) afforded 3.07 g of an oil. Thedihydrochloride was prepared by dissolving the oil in methanol. Additionof ethereal-HCl led to formation and subsequent precipitation of thesalt. Filtration followed by washing with ether and pentane gave6,7-dihydro-5-[3-(4-methyl-1-piperazinyl)-propyll-3-phenyl-1,2-benzisoxazol-4(5H)-one dihydrochloride, m.p. 237°- 240° C. (dec).

Analysis: Calculated for C₂₁ H₂₉ Cl₂ N₃ O₂ : 59.16%C, 6.86%H, 9.85%N.Found: 59.06%C, 6.61%H, 9.81%N.

EXAMPLE 13 6,7-Dihydro-3-phenyl-5-[3-(1-piperidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (4.00g) and dimethylformamide (69 ml) was added diisopropylethyl amine (4.81ml), piperidine (1.50 ml) and sodium iodide (0.62 g) at room temperaturewith stirring. The reaction was flushed with nitrogen and warmed at83°-85° C. for 7-8 hours. Upon cooling to room temperature, water andethyl acetate were added to the reaction mixture. The layers wereseparated and the aqueous layer extracted twice with ethyl acetate andonce with ether. The combined organic layers were washed with brine anddried (MgSO₄). Filtration and concentration gave the crude product.Purification via flash column chromatogaphy (silica gel, 2%triethylamine/0-4% methanol/ethyl acetate) afforded 2.30 g of theproduct. Recrystallization from ether/pentane yielded6,7-dihydro-3-phenyl-5-[3-(1-piperidinyl)-propyll-1,2-benzisoxazol-4(5H)-one,m.p. 91.5°-93.5° C.

Analysis: Calculated for C₂₁ H₂₆ N₂ O₂ : 74.53%C, 7.74%H, 8.28%N. Found:74.69%C, 7.81%H, 8.25%N.

EXAMPLE 146,7-Dihydro-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-onedihydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.00g) and dimethylformamide (80 ml) was added diisopropylethyl amine (4.53ml), 1-(2-methoxyphenyl)piperazine hydrochloride (2.62 g) and sodiumiodide (1.6 g) at room temperature with stirring. The reaction wasflushed with nitrogen and warmed at 85°-87° C. for 7.5 hours. Uponcooling to room temperature, water and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous layerextracted three times with ethyl acetate and once with ether. Thecombined organic layers were washed with brine and dried (K₂ CO₃).Filtration and concentration gave the crude amine product. Purificationvia flash column chromatography (silica gel, 1% triethylamine/0-0.5%methanol/ether) and another column (alumina, ether) afforded 1.50 g ofthe amine product. The dihydrochloride was prepared in ether withethereal HCl. The resulting precipitate was filtered and washed withether/pentane to yield 6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-onedihydrochloride, m.p. 182°-185° C.

Analysis: Calculated for C₂₇ H₃₃ Cl₂ N₃ O₃ : 62.55%C, 6.42%H, 8. 10%N.Found: 62.30%C, 6.39%H, 8.05%N.

EXAMPLE 15 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-onehydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (6.13g) and dimethylforinamide (DMF) (200 ml) was added diisopropylethylamine (9.23 ml), 4-(4-fluorobenzoyl)piperidine hydrochloride (5.67 g)and sodium iodide (3.18 g) at room temperature with stirring. Thereaction was flushed with nitrogen and warmed at 85°-87° C. for 7 hours.Upon cooling to room temperature, water and ethyl acetate were added tothe reaction mixture. The layers were separated and the aqueous layerextracted three times with ethyl acetate and once with ether. Thecombined organic layers were washed with brine and dried (K₂ CO₃).Filtration and concentration gave the crude amine product. Purificationvia flash column chromatography (silica gel, 1 % triethylamine (Et₃N)/2% methanol/ether), another column (silica gel, 2% Et₃ N/ether) andanother column (alumina, ether) afforded 2.60 g of the amine product asan oil. The hydrochloride was prepared in ether and methanol withethereal HCl and pentane. The resulting product was recovered byfiltration and washed with pentane to yield6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-onehydrochloride, m.p. 194°-197° C.

Analysis: Calculated for C₂₈ H₃₀ ClFN₂ O₃ : 67%C, 6.08%H, 5.64%N. Found:67.40%C, 6.05%H, 5.58%N.

EXAMPLE 165-[3-(4-(4-Chlorophenyl)-4-hydroxy-piperidinyl)-propyl]-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.02g) and DMF (170 ml) was added diisopropylethyl amine (7.50 ml),4-(4-chlorophenyl)-4-hydroxypiperidine (4.03 g) and sodium iodide (2.59g) at room temperature with stirring. The reaction was flushed withnitrogen and warmed to 78°-80° C. for 11 hours. Upon cooling to roomtemperature, water and ethyl acetate were added to the reaction mixture.The layers were separated and the aqueous layers extracted three timeswith ethyl acetate. The combined organic layers were washed with brineand dried (MgSO₄). Filtration and concentration gave the crude amineproduct. Purification via flash chromatography (silica gel, 2% Et₃N/ether) afforded 2.60 g of the desired product as an oil. Addition ofether, heat, and slow evaporation gave a powder. The ether was thendecanted and the powder was washed with pentane to yield5-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidinyl)-propyl]-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 147°-148° C.

Analysis: Calculated for C₂₇ H₂₉ ClN₂ O₃ : 69.74%C, 6.29%H, 6.02%N.Found: 69.75%C, 6.23%H, 5.98%N.

EXAMPLE 17 6,7-Dihydro-5-[3-(4-(2-keto-1-benzimidazolinyl)-1-piperidinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (4.19g) and DMF (150 ml) was added diisopropylethyl amine 6.31 ml),4-(2-keto-1 - benzimidazolinyl)piperidine (3.46 g) and sodium iodide(2.17 g) at room temperature with stirring. The reaction was heated at78° C. under nitrogen atmosphere with stirring (11 hours). Upon coolingto room temperature, water and ethyl acetate were added to the reactionmixture. The layers were separated and the aqueous layer extracted threetimes with ethyl acetate and once with ether. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via flashchromatography (silica gel, 1% methanol/2%Et₃ N/ether) afforded 1.90 gof6,7-dihydro-5-[3-(4-(2-keto-1-benzimidazolinyl)-1-piperidinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 212°-218° C.

Analysis: Calculated for C₂₈ H₃₀ N₄ O₃ : 71.47%C, 6.43%H, 1 1.91%N.Found: 71.25%C, 6.51%H, 11.63%N.

EXAMPLE 185-(3-Chloropropyl)-6.7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

In 500 ml anhydrous THF was dissolved 15.0 g6,7-dihydro-3-(2-fluorophenyl) -1,2-benzisoxazol-4(5H)-one undernitrogen atmosphere with stirring. The solution was cooled to -78° C.and 65.0 ml lithium diisopropylamide (1.5 molar in cyclohexane) wasadded dropwise. The resulting solution was stirred for ten minutes at-78° C. and 9.10 ml 1-chloro-3-iodopropane was added. Upon warming toroom temperature, the reaction mixture was poured into water and ether.The layers were separated and the aqueous phase was extracted threetimes with dichloromethane and once with ether. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product as an oil. Column chromatography onsilica gel (start with 10% dichloromethane in hexane and graduallyincrease polarity to 100% dichloromethane) gave 5.30 g of5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-oneas an oil.

b. 6,7-Dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl) -propyl]-1,2-benzisoxazol-4(5H)-one dihydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (5.0 g) and DMF (125 ml) was addeddiisopropylethyl amine (7.09 ml), 1-(2-methoxyphenyl)piperazine (3.44 g)and sodium iodide (2.44 g) at room temperature with stirring. Thereaction was flushed with nitrogen and warmed to 78° C. for 8 hours.Upon cooling to room temperature, water and ethyl acetate were added tothe reaction mixture. The layers were separated and the aqueous layerextracted three times with ethyl acetate. The combined organic layerswere washed with brine and dried (MgSO₄). Filtration and concentrationgave the crude amine product. Purification via flash chromatography(silica gel, 1% triethylamine/2% methanol/ether) afforded 1.90 g of theamine product as an oil. The dihydrochloride was prepared in ether withethereal HCl. Addition of pentane gave a precipitate which was filteredand washed with ether/pentane to yield6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-methoxyphenyl) -1-piperazinyl)propyl]-1,2-benzisoxazol-4(5H)-one dihydrochloride, m.p. 147°-150° C.

Analysis: Calculated for C₂₇ H₃₀ FN₃ O₃ ·2HCl: 60.45%C, 6.01%H, 7.83%N.Found: 60.8 1%C, 6.02%H, 7.89%N.

EXAMPLE 19 6,7-Dihydro-5-[3-4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (4.24 g) and DMF (125 ml) was addeddiisopropylethyl amine (6.01 ml), 4-(4-fluorobenzoyl)piperidinehydrochloride (3.69 g) and sodium iodide (2.07 g) at room temperaturewith stirring. The reaction was flushed with nitrogen and warmed to 78°C. for 8 hours. Upon cooling to room temperature, water, brine and ethylacetate were added to the reaction mixture. The layers were separatedand the aqueous layer extracted four times with ethyl acetate. Thecombined organic layers were washed with brine and dried (MgSO₄).Filtration and concentration gave the crude amine product. Purificationvia flash chromatography (silica gel, 2% triethylamine (Et₃ N)/ether)afforded 1.87 g of the amine product as an oil. The hydrochloride wasprepared in ether with methanolic HCl. The resultant hydrochlorideprecipitate was filtered and washed with ether/pentane to yield6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H) -onehydrochloride, m.p. 187°-190° C.

Analysis: Calculated for C₂₈ H₂₈ F₂ N₂ O₃ ·HCl: 65.30%C, 5.68%H, 5.44%N.Found: 65.49%C, 5.74%H, 5.44%N.

EXAMPLE 20 a.5-(3-Chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

In a similar manner to that of Examples 7a-d starting with4-fluorobenzaldehyde oxime, the starting ketone is prepared. In 170 mlanhydrous THF was dissolved 4.0 g6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogenatmosphere with stirring. The solution was cooled to -78° C. and 17.3 mllithium diisopropylamide (1.50 molar in cyclohexane) was added dropwise.The resulting solution was stirred for ten minutes at -78° C. and 2.2 ml1-chloro-3-iodopropane was added. Upon warming to room temperature, thereaction mixture was poured into water and the layers were thenseparated. The aqueous phase was extracted twice with dichloromethaneand once with ether. The combined organic layers were washed with brineand dried (MgSO₄). Filtration and concentration gave the crude product.Column chromatogaphy on silica gel (start with 10% dichloromethane inhexane and gradually increase polarity to 100% dichloromethane) gave 4.2g of5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one.

b. 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl-1-piperidinyl)-propyl]-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one(4.2 g) and DMF (120 ml) was added diisopropylethyl amine (7.15 ml),4-(4-fluorobenzoyl)piperidine hydrochloride (3.98 g) and sodium iodide(2.05 g) at room temperature with stirring. The reaction was flushedwith nitrogen and warmed to 80° C. for 12.5 hours. Upon cooling to roomtemperature, water and ethyl acetate were added to the reaction mixture.The layers were separated and the aqueous layer extracted three timeswith ethyl acetate. The combined organic layers were washed with brineand dried (MgSO₄). Filtration and concentration gave the crude amineproduct. Purification via flash chromatography (silica gel, 2% Et₃N/ether) afforded 2.60 g of the amine as an oil. The hydrochloride wasprepared in ether with methanolic HCl. The resultant hydrochlorideprecipitate was filtered and washed with ether/pentane to yield6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(4-fluorophenyl) -1,2-benzisoxazol-4 (5H)-onehydrochloride, m.p. 193°-195° C.

Analysis: Calculated for C₂₈ H₂₉ ClF₂ N₂ O₃ 65.30%C, 5.68%H, 5.44%N.Found: 64.94%C, 5.66%H, 5.39%N.

EXAMPLE 21 a. 3-(4Chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one

In a similar manner to that of Examples 7a-d starting with4-chlorobenzaldehyde oxime, the starting ketone is prepared. In 220 mlanhydrous THF was dissolved 8.1 g3-(4-chlorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one under nitrogenatmosphere with stirring. The solution was cooled to -78° C. and 32.8 mllithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise.The resulting solution was stilted for fifteen minutes at -78° C. and4.6 ml 1-chloro-3-iodopropane was added. Upon warming to roomtemperature, the reaction mixture was poured into water and the layerswere separated. The aqueous phase was extracted twice withdichloromethane and once with ether. The combined organic layers werewashed with brine and dried (MgSO₄). Filtration and concentration gavethe crude product. Column chromatography on silica gel (start with 5%dichloromethane in hexane and gradually increase polarity to 100%dichloromethane) gave 5.2 g of3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one.

b. 3-(4-Chlorophgnyl)-6,7-dihydro-5-[3-(4-(4-fluoro-benzoyl)-1-piperidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (8.66 g) and DMF (270 ml) was addeddiisopropylethyl amine (14 ml), 4-(4-fluorobenzoyl)piperidinehydrochloride (7.81 g) and sodium iodide 0.2 g) at room temperature withstirring. The reaction mixture was flushed with nitrogen and warmed to80° C. for 12 hours. Upon cooling to room temperature, water and ethylacetate were added to the reaction mixture. The layers were separatedand the aqueous layer was extracted three times with ethyl acetate. Thecombined organic layers were washed with brine and dried (MgSO₄).Filtration and concentration gave the crude product. Purification viaflash chromatography (silica gel, 2% Et₃ N/ether) afforded 3.25 g of theproduct as an oil. Trituration with dry ether solidified the product toyield 3-(4-chlorophenyl)-6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl) propyl]-1,2-benzisoxazol-4(5H)-one, m.p. 134°-135° C.

Analysis: Calculated for C₂₈ H₂₈ ClFN₂ O₃ 67.94%C, 5.70%H, 5.66%N.Found: 67.52%C, 5.66%H, 5.55%N.

EXAMPLE 223-(4-Chlorophenyl)-6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-onedihydrochloride

To a solution consisting of3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (7.13 g) and DMF (1 25 ml) was addeddiisopropylethyl amine (9.6 ml), 1- (2-methoxyphenyl) piperazine (4.24g) and sodium iodide (0.17 g) at room temperature with stirring. Thereaction mixture was flushed with nitrogen and warmed to 80° C. for 10hours. Upon cooling to room temperature, water and ethyl acetate wereadded to the reaction mixture. The layers were separated and the aqueouslayer extracted three times with ethyl acetate. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude amine product. Purification via flashchromatography (silica gel, 2% Et₃ N/ether) afforded 3.31 g of the amineproduct as an oil. The dihydrochloride was prepared in ether withethereal HCl. The resultant salt precipitate was filtered and washedwith pentane to yield3-(4-chlorophenyl)-6,7-dihydro-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one dihydrochloride, m.p. 208°-210° C.

Analysis: Calculated for C₂₇ H₃₂ Cl₃ N₃ O₃ : 58.65%C, 5.83%H, 7.60%N.Found: 58.93%C, 5.90%H, 7.53%N.

EXAMPLE 233-(4-Chlorophenyl)-5-(3-chloropropyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole

In 100 ml of anhydrous THF was dissolved 6.0 g 3-(4-chlorophenyl)-5-(3-chloropropyl)-1,2-benzisoxazol-4(5H)- one under nitrogenatmosphere. The solution was cooled to -5° C. and 840 mg sodiumborohydride was added. The reaction mixture was stirred at 0° C. for 45minutes and then warmed to 10° C. for 20 minutes. After cooling to 0°C., the reaction mixture was quenched with aqueous NH₄ Cl (saturated)then extracted with ether. The organic layer was dried (MgSO₄), filteredand concentrated in vacuo to give 6.0 g of3-(4-chlorophenyl)-5-(3-chloropropyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazoleas an oil.

3-(4-Chlorophenyl)-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-4-hydroxy-46,7-tetrahydro -1,2-benzisoxazole

To a solution consisting of3-(4-chlorophenyl)-5-(3-chloropropyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (5.15 g) and DMF (110 ml) wasadded diisopropylethyl amine (6.0 ml), 4-(4-fluorobenzoyl)piperidinehydrochloride (4.29 g) and sodium iodide (117 mg) at room temperaturewith stirring. The reaction was flushed with nitrogen and warmed to 80°C. for 12 hours. Upon cooling to room temperature, water and ethylacetate were added to the reaction mixture. The layers were separatedand the aqueous layer was extracted three times with ethyl acetate. Thecombined organic layers were washed with brine and dried (MgSO₄).Filtration and concentration gave the crude product. Purification viaflash chromatography (silica gel, 2% Et₃ N/ether) afforded 1.11 g of theproduct. Recrystallization from ethyl acetate/ethanol gave3-(4-chlorophenyl)-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole,m.p. 152°-155° C.

Analysis: Calculated for C₂₈ H₃₀ ClFN₂ O₃ : 67.67%C, 6.08%H, 5.64%N.Found: 67.3 1%C, 6.1 1%H, 5.56%N.

EXAMPLE 246,7-Dihydro-3-(4-fluorophenyl)-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (8.44 g) and DMF (I 30 ml) was addeddiisopropylethyl amine (9.6 ml), 1-(2-methoxyphenyl)piperazine (6.87 g)and sodium iodide (0.21 g) at room temperature with stirring. Thereaction was flushed with nitrogen and warmed to 80° C. for 12 hours.Upon cooling to room temperature, water and ethyl acetate were added tothe reaction mixture. The layers were separated and the aqueous layerwas extracted three times with ethyl acetate. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude amine product. Purification via flashchromatography (silica gel, 2% Et₃ N/ether) afforded 5.0 g of the amineproduct as an oil. Trituration with dry ether and pentane solidified theproduct which was filtered and washed with pentane to yield6,7-dihydro-3-(4-fluorophenyl)-5-[3-(4-(2-methoxyphenyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one, m.p. 107°-108° C.

Analysis: Calculated for C₂₇ H₃₀ FN₃ O₃ : 69.96%C, 6.52%H, 9.06%N.Found: 70.07%C, 6.57%H, 8.98%N.

EXAMPLE 25 3-(4-Chlorophenyl)-6,7-dihydro-5-[3-(4-fluorophenyl)methyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of 3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (5.2 g) and DMF (130 ml) wasadded bis-(4fluorophenyl)methylpiperazine (6.0 g), diisopropylethylamine (3.4 ml) and sodium iodide (0.12 g,) at room temperature withstirring. The reaction was flushed with nitrogen and warmed to 80° C.for 12 hours. Upon cooling to room temperature, water and ethyl acetatewere added to the reaction mixture. The layers were separated and theaqueous phase extracted three times with ethyl acetate. The combinedorganic layers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude amine product. Purification via flashchromatography (silica gel, 2% Et₃ N/ether) afforded 2.6 g of the amineproduct as an oil. Trituration with dry ether and pentane solidified theproduct which was filtered and washed with pentane to yield3-(4-chlorophenyl)-6,7-dihydro-5-[3-(4-(bis-(4-fluorophenyl)methyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one, m.p. 150°-152° C.

Analysis: Calculated for C₃₃ H₃₂ ClF₂ N₃ O₂ : 68.80%C, 5.60%H, 7.29%N.Found: 68.92%C, 5.73%H, 7.11%N.

EXAMPLE 26 a.5-(3-Chloropropyl)-6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

In a similar manner to that of Examples 7a-d starting with3-fluorobenzaldehyde oxime, the starting ketone is prepared. In 200 mlanhydrous THF was dissolved 11.4 g6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogenatmosphere with stirring. The solution was cooled to -78° C. and 49.4 mllithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise.The resulting solution was stirred for ten minutes at -78° C. and 6.4 ml1-chloro-3-iodopropane was added. Upon warming to room temperature, thereaction mixture was poured into water and ether. The layers wereseparated and the aqueous phase was extracted twice with dichloromethaneand once with ether. The combined organic layers were washed with brineand dried (MgSO₄). Filtration and concentration gave the crude product.Column chromatography on silica gel (start with 10% dichloromethane inhexane and gradually increase polarity to 100% dichloromethane) gave 4.5g of 5-(3-chloropropyl)-6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one.

b. 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl) -1-piperidinyl)propyl]-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride

To a solution of5-(3-chloropropyl)-6,7-dihydro-3-(3-fluorophenyl)-2-benzisoxazol-4(5H)-one(4.50 g) and DMF (100 ml) was added anhydrous potassium carbonate (6.10g), 4-(4-fluorobenzoyl)piperidine hydrochloride (4.30 g) and sodiumiodide (0.11 g) at room temperature with stirring. The reaction wasflushed with nitrogen and warmed to 80° C. for 12 hours. Upon cooling toroom temperature, water and ethyl acetate were added to the reactionmixture. The layers were separated and the aqueous layer was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine and dried (MgSO₄). Filtration and concentration gave thecrude amine product. Purification via flash chromatography (silica gel,2% Et₃ N/ether) afforded 2.1 g of the amine product as an oil. Thehydrochloride was prepared in isopropanol with ethereal HCl. The saltwas filtered and washed with pentane to yield6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride, m.p. 186°-188° C.

Analysis: Calculated for C₂₈ H₂₉ ClF₂ N₂ O₃ : 65.30%C, 5.68%H, 5.44%N.Found: 65.22%C, 5.75%H, 5.36%N.

EXAMPLE 27 a.5-(3-Chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol-4(5H)-one

In 140 ml anhydrous THF was dissolved 4.20 g5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-oneunder nitrogen atmosphere, with stirring. The solution was cooled to-78° C. and 14.0 ml lithium diisopropylamide (1.5 molar in cyclohexane)was added dropwise. The resulting solution was stirred for 10 minutes at-78° C. and 1.30 ml iodomethane was added. Upon warming to roomtemperature, the reaction mixture was poured into water and ether. Thelayers were separated and the aqueous phase was extracted two times withdichloromethane and once with ether. The combined organic layers werewashed with brine and dried (MgSO₄). Filtration and concentration gavethe crude product as an oil. Column chromatography on silica gel (starteluting with 10% dichloromethane in hexane and gradually increasepolarity to 100% dichloromethane) afforded 4.00 g of5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol-4(5H)-oneas an oil.

b. 6,7-Dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol -4(5H)-onehydrochloride

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol-4(5H)-one(4.5 g) and DMF (100 ml) was added diisopropylethyl amine (4.9 ml),4-(4-fluorobenzoyl)piperidine hydrochloride (4.9 g) and sodium iodide(0.10 g), at room temperature with stirring. The reaction was flushedwith nitrogen and warmed to 50° C. for 26 hours and then to 80° C. for 6hours. Upon cooling to room temperature, water and ethyl acetate wereadded to the reaction mixture, The layers were separated and the aqueouslayer extracted three times with ethyl acetate. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude amine product. Purification via flashchromatography (silica gel, 2% Et₃ N/ether) afforded 1.9 g of the amineproduct as an oil. The hydrochloride was prepared in ether with etherealHCl. Trituration with pentane precipitated the target product. The solidwas filtered and washed with pentane to yield 6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-(4-fluorophenyl)-7-methyl-1,2-benzisoxazol-4(5H)-onehydrochloride, m.p. 111°-113° C.

Analysis: Calculated for C₂₉ H₃₁ ClF₂ N₂ O₃ : 65.84%C, 5.91%H, 5.30%N.Found: 65.49%C, 6.11%H, 5.11%N.

EXAMPLE 28 6,7-Dihydro-5-[3-(4-(bis-(4-fluorophenyl)methyl)-1-piperazinyl) propyl]-3-(2-fluorophenyl)-1,2 benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (5.3 g) and DMF (100 ml) was added bis-(4-fluorophenyl)methylpiperazine (6.5 g), diisopropylethyl amine (6.0 ml)and sodium iodide (0.13 g) at room temperature with stirring. Thereaction was flushed with nitrogen and warmed to 80° C. for 15.5 hours.Upon cooling to room temperature, water and ethyl acetate were added tothe reaction mixture. The layers were separated and the aqueous phaseextracted three times with ethyl acetate. The combined organic layerswere washed with brine and dried (MgSO₄). Filtration and concentrationgave the crude amine product. Purification via flash chromatography(silica gel, 2% Et₃ N/ether) afforded 3.8 g of the amine product as anoil. Trituration with dry ether and pentane solidified the product whichwas filtered and washed with pentane to yield6,7-dihydro-5-[3-(4-(bis-(4-fluorophenyl)methyl)-1-piperazinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one,m.p. 95°-97° C.

Analysis: Calculated for C₃₃ H₃₂ F₃ N₃ O₂ : 70.83%C, 5.76%H, 7.51%N.Found: 70.84%C, 5.80%H, 7.41%N.

EXAMPLE 29 a. 5-Carbomethoxy-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

In a 600 ml anhydrous tetrahydrofuran was dissolved6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one (20.0 g) undernitrogen. The solution was cooled to -78° C. and 87 ml lithiumdiisopropylamide was added dropwise. The resulting solution was stirredfor ten minutes at -78° C. and 8.7 ml methyl chloroformate was added.Upon warming to room temperature, the reaction mixture was poured intowater and ethyl acetate. The layers were separated and the aqueous phasewas extracted three times with dichloromethane. The combined organiclayers were washed with brine, dried (MgSO₄), filtered and concentrated.Column chromatography on silica gel (starting with 10% dichloromethanein hexane and gradually increasing the polarity to 100% DCM) gave 13.5 gof crude product.

b. 5-Carbomethoxy-5-[4-(4-(4-fluorobenzoyl) -1-piperidinyl)-butyl)]-13-(2-fluorophenyl)-6,7- benzisoxazol-4(5H)-one oxalate

To a solution consisting of5-carbomethoxy-3-(2-fluorophenyl)6,7-dihydro-1,2-benzisoxazol -4(5H)-one(7.0 g,) and acetone (60 ml) was added potassium carbonate (13.4 g),1-bromo-4-chlorobutane (3.6 ml) and sodium iodide (360 mg) at roomtemperature with stirring. The reaction mixture was heated to reflux for6 hours. Upon cooling to room temperature water and ethyl acetate wereadded to the reaction mixture. The layers were separated and the aqueousphase was extracted three times with ethyl acetate. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via preparative HPLC(silica gel, 20% ethyl acetate/hexane) afforded 7.3 g of the product5-carbomethoxy-5-(4-chlorobutyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one.

To a solution consisting of the above product (7.3 g) in DMF (100 n-A)was added 4-(4-fluorobenzoyl)piperidine (5.2 g), potassium carbonate(3.5 g) and sodium iodide (140 mg) at room temperature with stirring.The flask was flushed with nitrogen and warmed to 80° C. for 10 hours.Upon cooling to room temperature, water and ethyl acetate were added tothe reaction mixture. The layers were separated and the aqueous phasewas extracted three times with ethyl acetate. The combined organiclayers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via flash columnchromatography (silica gel, 2% triethylamine/ether) afforded 3.6 g of anoil. The oxalate salt was prepared in ethanol. The resultant precipitatewas filtered and washed with ether/pentant to yield5-carbamethoxy-5-[4-(4-(4-fluorobenzoyl)-1-piperidinyl)-butyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)- one oxalate as an oil. The oxalatesalt was prepared in ethanol. The precipiate was filtered and washedwith ether/pentane, m.p. 208°-210° C.

Analysis: Calculated for C₃₃ H₃₄ F₂ N₂ O₉ : 61.87%C, 5.35%H, 4.37%N.Found: 61.64%C, 5.09%H, 4.28%N.

EXAMPLE 305-[3-[4-(6-Fluoro-1,2,benzisoxazol-3-yl)-1-piperidinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one oxalate

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisozaxol-4(5H)-one(3.4 g) and DMF (100 ml) was added6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.2 g), diisopropylethylamine (3.9 ml), and sodium iodide (83 mg) at room temperature withstirring. The flask was flushed with nitrogen and warmed at 80° C. for17 hours. Upon cooling to room temperature, water and ethyl acetate wereadded to the reaction mixture. The layers were separated and the aqueousphase extracted 3 times with ethyl acetate. The combined organic layerswere washed with brine and dried (MgSO₄). Filtration and concentrationgave the crude product. Purification via flash column chromatography(silica gel, 2% triethylamine) afforded 2.4 g of5-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-pipendinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4-(5H)-one,as an oil. The oxalate salt was prepared in ethanol with oxalic acid.The precipitate was filtered and washed with ether/pentane, m.p.201°-203° C.

Analysis: Calculated for C₃₀ H₂₉ F₂ N₃ O₇ : 61.96%C, 5.03%H, 7.23%N.Found: 61.80%C, 4.89%H, 7.20%N.

EXAMPLE 31 a. 4,5,6,7-Tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethyl ester

In 115 ml anhydrous tetrahydrofuran was dissolved 2.44 g of6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogen. Thesolution was cooled to -78° C. and 11.5 ml lithium diisopropylamide wasadded dropwise. The resultant solution was sniffed for 15 minutes at-78° C. and ethyl bromoacetate (2.6 ml) was added. Upon warming to roomtemperature, the reaction mixture was poured into water and ether. Thelayers were separated and the aqueous phase was extracted three timeswith dichloromethane and once with ether. The combined organic layerswere washed with brine and dried (MgSO₄). Flash column chromatography(30% ethyl acetate/hexane) gave 2.94 g of4,5,6,7-tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethylester

b.4-Hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole

In a 2 liter round-bottomed flask was dissolved4,5,6,7-tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethylester (3.0 g) in absolute ethanol (300 ml) at room temperature. Sodiumborohydride (6.07 g) was added and the solution was heated to reflux.The solution was cooled to room temperature, then diluted with saturatedNH₄ Cl until a solid appeared. The reaction mixture was basified to pH 9using 10% NAOH (aq.). The product, an oil, was extracted with ether andthe aqueous phase was extracted twice with ether. The combined organiclayers were washed with brine, dried (MgSO₄), filtered and concentratedto give 2.60 g of4-hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole.

c. 3-Phenyl-5-(2-tosyloxyethyl)-4-hydroxy -44,5,6,7-tetrahydro-1,2-benzisoxazole

In 30 ml pyridine was dissolved4-hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole(2.1 g) and the mixture was cooled to 0° C. Tosyl chloride (1.54 g) wasadded and the solution was stirred at 0° C. for 30 minutes. The reactionmixture was poured into ice water, then extracted four times with ether.The mixture was dried (Na₂ SO₄) and then concentrated at roomtemperature to yield 2.67 g of3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.

d.5-[2-(4-(4-Fluorobenzoyl)-1-piperidinyl)-ethyl]3-phenyl-6,7-dihydro-1,2-benzisoxazol-4(5H)-one hydrochloride

To a solution consisting of3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole(8.0 g) and DMF (100 n-il) was added diisopropylethyl amine (6.7 ml) and4-(4-fluorobenzoyl)piperidine hydrochloride (7.1 g) at room temperaturewith stirring. The flask was flushed with nitrogen and warmed to 80° C.for 4.5 hours. Upon cooling to room temperature, water and ethyl acetatewere added to the reaction mixture. The layers were separated and theaqueous phase was extracted 3 times with ethyl acetate. The combinedorganic layers were washed with brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via flash columnchromatography (silica gel, 2% triethylamine/ether) afforded 1.3 g of5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-phenyl-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.

To a solution of the above product (1.3 g) in DMF (25 ml) was added asolution of pyridinium dichromate (1.9 g) in DMF (10 ml). The flask wasflushed with nitrogen and allowed to stir at room temperature for 17hours under nitrogen atmosphere. The reaction mixture was poured intowater and ethyl acetate. The layers were separated and the aqueous phasewas extracted 4 times with ethyl acetate. The combined organic layerswere washed with brine and dried (MgSO₄). Filtration and concentrationgave the crude product. Purification via flash column chromatography(silica gel, 2% triethylamine/ether) afforded 0.8 g of5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-phenyl-6,7-dihydro-1,2-benzisoxazol-4(5H)-one.The colored impurities were removed by flushing the product thru aluminawith ether. The hydrochloride salt was prepared in isopropanol withethereal HCl. The precipitate was filtered and washed with pentane, m.p.211°-215° C.

Analysis: Calculated for C₂₇ H₂₈ ClFN₂ O₃ : 67.14%C, 5.84%H, 5.80%N.Found: 67.31%C, 6.03%H, 5.70%N.

EXAMPLE 325-[2-(4-(4-Fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorphenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-onesalicylate

To a solution consisting of5-(2-chloroethyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one(2.5 g) and DMF (85 ml) was added anhydrous potassium carbonate (0.6 g),diisopropylethyl amine (2.2 ml), 4-(4-fluorobenzoyl)piperidine (2.3 g)and potassium iodide (70 mg) at room temperature with stirring. Theflask was flushed with nitrogen and warmed to 80° C. for 19 hours. Uponcooling to room temperature, water and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous phase wasextracted 3 times with ethyl acetate. The combined organic layers werewashed with brine and dried (MgSO₄). Filtration and concentration gavethe crude product.

Purification via flash column chromatography (silica gel, 2%triethylamine/ether) afforded 1.5 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-(2-fluorphenyl)-6,7-dihydro-1,2-benzisoxazol-4-(5H)-one, as an oil. The product wasflushed thru alumina with ether. The salicylate was prepared in etherand the resulting salt was washed with ether/pentane, m.p. 80°-82° C.

Analysis: Calculated for C₃₄ H₃₂ F₂ N₂ O₆ : 67.76%C, 5.35%H, 4.65%N.Found: 67.26%C, 5.31%H, 4.78%N.

EXAMPLE 33 5-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-onehydrochloride

To a solution consisting of5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (1.36 g) and DMF (40 ml) was added anhydrouspotassium carbonate (0.3 g), diisopropylethyl amine (0.8 ml),3-piperazinyl-1,2-benzisothiazol (1.26 g) and potassium iodide (27 mg)at room temperature with stirring. The flask was flushed with nitrogenand warmed to 80° C. for 12 hours. Upon cooling to room temperature,water and ethyl acetate were added to the reaction mixture. The layerswere separated and the aqueous phase was extracted three times withethyl acetate. The combined organic layers were washed with brine anddried (MgSO₄). Filtration and concentration gave the crude product.Purification via flash column chromatography (silica gel, 20%triethylamine/ether) afforded 1.0 g of5-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-oneas a foam. The product was flushed through alumina with dichloromethane.The hydrochloride was prepared by dissolving the free amine withmenthanol and adding ethereal HCl. The salt was filtered and washed withpentane, m.p. 215° C. (dec.).

Analysis: Calculated for C₂₇ H₂₈ ClFN₄ O₂ S: 61.53%C, 5.35%H, 10.63%N.Found: 61.12%C, 5.34%H, 10.52%N.

EXAMPLE 34 6,7-Dihydro-5-[3-(4-(4-fluorophenyl) -1-piperazinyl)propyl]-3-(2-fluorophenyl)-I,2-benzisoxazol -4(5H)-one hydrochloridemonohydrate

To a solution consisting of5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (5.8 g) and DMF (100 ml) was added anhydrouspotassium carbonate (1.3 g), diisopropylethyl amine (4.9 ml),1-(4-fluorophenyl)piperazine (4.1 g) and potassium iodide (0.3 g) atroom temperature with stirring. The flask was flushed with nitrogen andwarmed to 80° C. for 13.5 hours. Upon cooling to room temperature, waterand ethyl acetate were added to the reaction mixture. The layers wereseparated and the aqueous phase was extracted 3 times with ethylacetate. The combined organic layers were washed with water twice,brine, and then dried (MgSO₄). Filtration and concentration gave thecrude product. Purification via flash column chromatography (silica gel,2% triethylamine/ether) afforded 4.0 g of6,7-dihydro-5-[3-(4-(4-fluorophenyl)-1-piperazinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The product was flushed thru alumina with ether.The hydrochloride was prepared in ether with ethereal HCl. Theprecipitate was filtered and washed with pentane, m.p. 161°-164° C.

Analysis: Calculated for C₂₆ H₃₀ ClF₂ N₃ O₃ : 61.72%C, 5.98%H, 8.30%N.Found: 61.70%C, 5.64%H, 8.27%N.

EXAMPLE 356,7-Dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyridyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.4 g) and DMF (100 ml) was added anhydrouspotassium carbonate (1.4 g), diisopropylethyl amine (5.4 ml),1-(2-pyridyl)piperazine (4.8 ml) and potassium iodide (0.4 g) at roomtemperature with stirring. The flask was flushed with nitrogen andwarmed to 80° C. for 16 hours. Upon cooling to room temperature, waterand ethyl acetate were added to the reaction mixture. The layers wereseparated and the aqueous phase was extracted three times with ethylacetate. The combined organic layers were washed with water twice, thenbrine and dried (MgSO₄). Filtration and concentration gave the crudeproduct. Purification via preparative HIPLC (silica gel, 3% methanol)afforded 4.2 g of6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyridyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one,as an oil which solidified upon standing. The product was recrystallizedfrom ether, m.p. 94°- 96° C.

Analysis: Calculated for C₂₅ H₂₇ FN₄ O₂ : 69.1 1%C, 6.26%H, 12.89%N.Found: 68.88%C, 6.25%H, 12.84%N.

EXAMPLE 36 1 5-[3-(4-(3-Chlorophenyl)-1-piperazinyl)-propyl]-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride

To a solution consisting of5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one(6.0 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4g), diisopropylethylamine (5.1 ml), 1-(3-chlorophenyl) piperazine (4.9g) and potassium iodide (0.3 g) at room temperature with stirring. Theflask was flushed with nitrogen and warmed to 80° C. for 18 hours. Uponcooling to room temperature, water and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous phase wasextracted 3 times with ethyl acetate. The combined organic layers werewashed with water twice, then brine twice, and dried (MgSO₄). Filtrationand concentration gave the crude product. Purification via flash columnchromatography (silica gel) afforded 3.4 g of 5-[3-(4-(3-chlorophenyl)-1-piperazinyl)propyl]-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as anoil. The hydrochloride was prepared in methanol with ethereal HCl. Theprecipitate was filtered and washed with anhydrous ether, m.p. 104°-106°C.

Analysis: Calculated for C₂₆ H₂₈ Cl₂ FN₃ O₂ : 61.91%C, 5.59%H, 8.33%N.Found: 61.75%C, 5.63%H, 8.30%N.

EXAMPLE 37 6,7-Dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyrimidyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one(7.3 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.6g), diisopropylethyl amine (6.2 ml), 1-(2-pyrimidyl) piperazine (5.8 g)and potassium iodide (0.4 g) at room temperature with stirring. Theflask was flushed with nitrogen and warmed to 80° C. for 16 hours. Uponcooling to room temperature, water and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous phase wasextracted 3 times with ethyl acetate. The combined organic layers werewashed with water twice, then brine and dried (MgSO₄). Filtration andconcentration gave the crude product. Purification via flash columnchromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyrimidyl)-1-piperazinyl)-propyl]-1,2-benzisoxazo1-4(5H)-one as an oil whichsolidified upon standing. Recrystalization with ether gave the productas a solid, m.p. 115°-117° C.

Analysis: Calculated for C₂₄ H₂₆ FN₅ O₂ : 66.19%C, 6.02%H, 16.08%N.Found: 65.96%C, 5.88%H, 15.94%N.

EXAMPLE 38 6,7-Dihydro-5-(4-(4-fluorobenzoyl)-1-piperidinyl)methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one

To a solution consisting of6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride (1. 86 g) in distilled water (18.5 ml) was added4-(4-fluorobenzoyl)piperidine hydrochloride (2.7 8 g) and potassiumcarbonate (0.80 g). The reaction mixture was heated at reflux for 3hours. Upon cooling to room temperature, ethyl acetate was added and thelayers were separated. The aqueous phase was extracted twice with ethylacetate. The combined organic layers were washed with brine and dried(MgSO₄). Filtration and concentration gave the crude product.Purification via flash column chromatography (silica gel, 40% ethylacetate/hexane) afforded 1.20 g of 6,7-dihydro-5-(4-(4-fluorobenzoyl)-1-piperidinyl)methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one. Thecompound was flushed through alumina with dichloromethane to give an oilwhich solidified on standing. The product was then recrystallized fromether/hexane, m.p. 99°-102° C.

Analysis: Calculated for C₂₆ H₂₄ F₂ N₂ O₃ : 69.32%C, 5.37%H, 6.22%N.Found: 69.41%C, 5.52%H, 6.20%N.

EXAMPLE 39 6,7-Dihydro-3-(2-fluorophenyl)-5-[(4-(2-methoxyphenyl)-1-piperazinyl)methyl]-1,2-benzisoxazol-4(5H)-one maleate

To a solution consisting of6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-onehydrochloride (2.40 g) in distilled water (24 ml) was added1-(2-methoxyphenyl)piperazine hydrochloride (3.38 g) and potassiumcarbonate (1.02 g) at room temperature with stirring. The resultingreaction mixture was heated to reflux for 25 min. and allowed to cool toroom temperature. Diethyl ether was then added and the layers separated.The aqueous phase was extracted twice with ether. The combined organicswere washed with brine and dried (Na₂ SO₄). Filtration and concentrationgave the crude product. Purification via flash column chromatography(silica gel, ether) afforded 2.45 g of6,7-dihydro-3-(2-fluorophenyl)-5-(4-(2-methoxyphenyl)-1-piperazinyl)methyl-1,2-benzisoxazol-4(5H)-oneas a foam. The compound was flushed thru alumina with dichloromethane togive an oil. The maleate was prepared in ethanol and the resulting saltwas washed with ether, m.p. 153°-155° C.

Analysis: Calculated for C₂₉ H₃₀ FN₃ O₇ : 63.15%C, 5.48%H, 7.62%N.Found: 63.04%C, 5.53%H, 7.56%N.

EXAMPLE 40 a.5-(3-Chloropropyl)-6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one

In 100 ml anhydous THF was dissolved6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one (2.2 g) under nitrogen.The solution was cooled to 0° C. and 10.2 ml lithium diisopropylamidewas added dropwise. The solution was stirred at 0° C. for 2.5 hours andquenched with 1-chloro-3-iodopropane (1.6 ml). The solution was removedfrom the ice bath and warmed to 40° C. under nitrogen. Upon cooling toroom temperature, the reaction mixture was poured into water and ether.The layers were separated and the aqueous phase was extracted threetimes with dichloromethane and once with ether. The combined organiclayers were washed once with water and salt brine, dried (MgSO₄),filtered and concentrated. Flash column chromatography on silica gel(15% ethyl acetate/hexane) gave 850 mg of5-(3-chloropropyl)-6,7-dihydro-3-methyl -1,2-benzisoxazol-4(5H)-one.

b. 6,7-Dihydro-5-13-(4-(4-fluorobenzoyl) -1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one

To a solution consisting of5-(3-chloropropyl)-6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one (0.85g) and DMF (20 ml) was added anhydrous potassium carbonate (0.52 g)diisopropylethyl amine (0.33 ml), 4-(4-fluorobenzoyl)piperidine (0.92 g)and potassium iodide (62 mg) at room temperature with stirring. Theflask was flushed with nitrogen and warmed to 80° C. for 24 hours. Uponcooling to room temperature, water and ethyl acetate were added to thereaction mixture. The layers were separated and the aqueous phase wasextracted 3 times with ethyl acetate. The combined organic layers werewashed with water twice, then brine. The organic phase was then dried(MgSO₄), filtered, and concentrated to give the crude product.Purification via flash column chromatography (silica gel, 2%triethylamine/ether) afforded 0.70 g of6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. Theproduct was dissolved and flushed through alumina with dichloromethane.Recrystallization with ether/hexane gave the product as a solid, m.p.81°-83° C.

Analysis: Calculated for C₂₃ H₂₇ FN₂ O₃ : 69.33%C, 6.83%H, 7.03%N.Found: 69.51%C, 6.65%H, 7.01%N.

We claim:
 1. The compound which is6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one.
 2. An antipsychotic composition which comprises a compoundas defined in claim 1, present in an amount sufficient to produce anantipsychotic effect, and a pharmaceutically acceptable carriertherefor.
 3. A method of treating psychoses which comprisesadministering to a mammal in need thereof an effective amount of thecompound as defined in claim
 1. 4. An analgesic composition whichcomprises a compound as defined in claim 1, present in an analgesicallyeffective amount, and a pharmaceutically acceptable carrier therefor. 5.A method of alleviating pain which comprises administering to a mammalin need thereof an effective amount of the compound as defined in claim1.